Objective

Most older adults have multiple chronic diseases (multimorbidity) and multiple medications (polypharmacy).However, multimorbid patients are often excluded from clinical trials and most guidelines address diseases inisolation. Inappropriate drug prescription and poor drug compliance are common and contribute to up to 30% ofhospital admissions. OPERAM investigators developed STOPP/START criteria to detect inappropriate drug use,both over- and underuse. Applying these criteria limits unnecessary polypharmacy and reduces underuse of indicatedmedications, but it remains uncertain whether systematic pharmacotherapy optimisation can improve clinicaloutcomes and reduce costs.We propose a multicentre randomised controlled trial to assess the impact of a userfriendlysoftware-assisted intervention to optimise pharmacotherapy and to enhance compliance in 1900 multimorbidpatients aged ≥75 years. Outcomes will include drug-related hospital admissions, health care utilisation, quality of life,patient preferences and cost-effectiveness. We will also perform several network meta-analyses (NMA) to providenew comparative evidence on the most effective and safest pharmacological and non-pharmacological interventionsto reduce common causes of preventable hospital admissions (e.g. falls, fractures, bleeding). Therapy optimisation inthe multimorbid elderly, enhanced compliance and discontinuation of less effective interventions have the potentialto improve clinical, quality of life and safety outcomes, while reducing costs. We will provide a structured methodwith practical software solutions for optimal prescribing and new comparative evidence from NMAs for addressingmultimorbidity and polypharmacy by means of customised, patient-centred guidelines. OPERAM ultimately aimsat better healthcare delivery in primary and hospital care, based on effective, safe, personalised and cost-effectiveinterventions that can be applied to the rapidly growing older population in Europe.

Many older adults have multiple chronic diseases (multimorbidity) and directly related multiple medications (polypharmacy). However, multimorbid older patients are often excluded from clinical trials, and most guidelines address diseases in isolation. Inappropriate drug prescription and poor drug compliance are common in older people, contribute to up to 30% of hospital admissions, and are related to morbidity and costs. The overall aim of OPERAM is to optimize existing pharmacological and nonpharmacological therapy, primarily aimed at reducing avoidable hospital admissions among the older population with multimorbidity.

OPERAM is divided into 9 work packages, including partners from Belgium, Germany, Greece, Italy, Ireland, Switzerland, and the Netherlands. The core part of the project is the conduct of a large-scale cluster RCT using the STRIP intervention versus usual pharmaceutical care to examine the effect of pharmacotherapy optimization on clinical outcomes (WP1-4 and 7), principally unscheduled drug-related admissions (the primary endpoint). The coordination of the RCT is the responsibility of WP1 (Clinical Trial Coordination), which set up a Trial Coordinating Centre (TCC) to ensure a uniform operation of all participating centres according to a high standard by providing the necessary documents and supportive infrastructure during the trial preparation and conduction phase. At the end of the third reporting period, 2009 patients have been included in the RCT. The recruitment process was completed on 4th of October 2018. The patients have been assigned to either an intervention or a control cluster, depending on the allocation of their prescribing physician. Patients who were assigned to a cluster in the intervention arm received the STRIP intervention as it has been defined by WP3. Each patient is followed-up by phone at 2, 6 and 12 months. At the end of this reporting period 1837/1669/1097, patients have been followed-up for 2/6/12 months. Dedicated, specially trained teams have adjudicated 1066 of 1580 documented unscheduled hospitalizations. To optimize reliability, a centralized system for monitoring of drug-related hospital admissions was initiated. In order to gain an in-depth understanding of patient experience of hospital-initiated medication changes, a mixed methods study combining both qualitative and quantitative data was conducted. Training and supervision of adjudication activities is being conducted as part of WP4. The implemented quality assurance system includes monitoring of key performance indicators, on-site monitoring and central data monitoring. Data entry is continuously monitored and the sites are provided with ongoing feedback on potential irregularities. Quality assurance activities are conducted as specified in the monitoring and the data management and validation plan (WP1). There has been further analysis on how to process user feedback semi-automatically from within a clinical decision support system (CDDS) or recommender context by means of a user behaviour mining approach in order to improve STRIPA’s efficiency (WP2). A specific protocol for falls and fall related fractures in the elderly was finalized and will be submitted to PROSPERO in June 2019 (WP5). The statistical analysis plan has been finalized and all analyses can be conducted upon receipt of the data. A review manuscript is being prepared for submission to a medical statistics journal. This manuscript will include the results of the empirical review of methodological papers with complex interventions (WP6). Resources in the third period have been applied to the programming and testing of the cost-effectiveness analysis; coordination of contributions of non-Swiss OPERAM sites; and collection of unit cost data as well as the preparations for the main cost-effectiveness analysis which are progressing according to plan. The analysis will be performed as soon as the database is locked i.e. in the fourth reporting period (WP7).OPERAM maintained its dissemination activities and its public visibility. Ten Analysis Plans and four manuscripts for publications and sub-studies were reviewed and approved by the OPERAM Publication Committee. Five scientific publications have been published and the public website has been continuously updated (WP8).All deliverables have been achieved according to plan and schedule, and related reports have been submitted to the EC. Several meetings and teleconferences with all project partners have taken place for the purpose of close project navigation and progress monitoring. A Contract Amendment has been prepa

OPERAM aims to add important and urgently needed evidence on the optimal pharmacotherapeutic management of multimorbid elderly people with polypharmacy and its impact on relevant clinical outcomes as well as its cost-effectiveness. To date, different screening tools have been developed to assess medication misuse, underuse and overuse; their effect on clinical outcomes must be assessed within the trial before their practicability can be assessed for routine clinical use. Our proposal aims to assess the effectiveness of an improved version of the existing STRIPA designed to systematically optimize polypharmacy among multimorbid elderly patients and improve their clinical outcomes. If shown to be effective, optimization of pharmacotherapy in this rapidly growing patient population could lead to major improvements in the care of older European citizens and significantly improve cost-effectiveness of prescription pharmacotherapy. The design of the OPERAM RCT aims to overcome the limitations of previous studies assessing the impact of pharmacotherapy optimization on clinical outcomes. The novel aspects of the concept implemented in the OPERAM RCT include: (i) a large sample size, (ii) inclusion of older patients with multimorbidity and polypharmacy, (iii) a structured assessment of medication at hospital admission, (iv) having a follow-up duration of one year, (v) cluster randomisation at the physician level to avoid contamination, and (vi) adjudication of outcomes by an independent and blinded adjudication committee. Furthermore, a recommendation sheet with rationale for prescription medication change recommendations was applied and discussed face-to-face with the prescribing physician in order to increase implementation rates. A qualified team comprising a pharmacist and a physician performed patient counselling in order to increase patients’ compliance to the recommendations. Finally, a recommendation sheet with rationale for recommendations for the general practitioner (GP) was applied to better communicate medication changes during hospitalization and to avoid discontinuation of newly prescribed medication or resumption of previously discontinued medications by patients’ GPs after discharge. An important feature of the OPERAM RCT is the multi-country study design with patient recruitment in Belgium, Ireland, The Netherlands and Switzerland.